Proton pump inhibitors (PPIs) and clopidogrel share common metabolic pathways mediated by cytochrome P450 enzymes (2C19) in the liver. Cytochrome P450 polymorphisms are associated with greater platelet aggregability, clopidogrel resistance and risk of cardiovascular events. Studies have reported that omeprazole reduces the inhibitory effect of clopidogrel on platelet aggregation and that clopidogrel resistance is associated with recurrent atherothrombotic events following myocardial infarction.

In a retrospective cohort study of 8205 patients with acute coronary syndrome (ACS) who were discharged on clopidogrel, Ho et al found that concomitant use of PPIs and clopidogrel was significantly associated with rehospitalization for ACS and revascularization procedures, but not all-cause mortality (see table). Data for cardiovascular mortality specifically were not available. They used multivariable logistic regression to adjust for demographics, comorbidities and presentation and treatment of ACS and followed patients for 521 days (median).

Outcome

Clopidogrel without PPI

(%)

Clopidogrel with PPI

(%)

Adjusted odds ratio

(95% CI)

Death or rehospitalization for ACS

20.8

29.8

1.25 (1.11-1.41)

Rehospitalization for ACS

6.9

14.6

1.86 (1.57-2.20)

Revascularization procedures

11.9

15.5

1.49 (1.30-1.71)

All-cause mortality

16.6

19.9

0.91 (0.80-1.05)

Periods of use of clopidogrel plus PPI (compared with those of clopidogrel without PPI) were associated with higher risk of the combined endpoint of rehospitalization for ACS or all-cause mortality (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). This association remained significant after exclusion of patients with previous gastrointestinal bleeding, patients with any bleeding during or after hospitalization, or patients prescribed H2-antagonists during follow-up, and after accounting for clustering of patients within hospitals. There was a consistent association between omeprazole (OR, 1.24; 95% CI, 1.08-1.41) and rabeprazole (OR, 2.83; 95% CI, 1.96-4.09) with adverse outcome. The association with other PPIs was not explored given small patient numbers.

However, the retrospective observational study design has inherent limitations and one should not infer causality from an association. The expert consensus document by the American College of Cardiology, American Heart Association and American College of Gastroenterology (2008), which pre-dated the study by Ho et al, had recommended that PPIs be the preferred agents for treatment and prophylaxis of aspirin-associated gastrointestinal injury in high-risk patients (history of ulcer disease, gastrointestinal bleeding, dual anti-platelet therapy or indication for concomitant anticoagulant therapy). Recently, however, the European Medicines Agency (EMEA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) recommended against concomitant use of PPIs with clopidogrel unless essential. Alternative medications, such as H2-antagonists, should be considered.

While the findings of Ho et al are supported by other unpublished data, they conflict with analyses from two randomized trials, CREDO and TRITON. An analysis of the CREDO trial found similar risk reductions with clopidogrel, regardless of whether or not patients were taking PPIs. In addition, in the TRITON trial, prasugrel, thought to be unaffected by PPI interactions, was not associated with a larger benefit over clopidogrel in patients taking PPIs, compared with those not taking PPIs. Concerns about other drugs thought to interact with clopidogrel, such as atorvastatin and calcium channel blockers, have been raised before, but disproved when randomized studies were analyzed.

While the COGENT-1 trial, a randomised controlled trial evaluating the combination of clopidogrel and omeprazole to reduce the incidence of gastrointestinal side effects, was recently stopped prematurely due to financial issues, ongoing trials of clopidogrel are tracking PPI use, such as CURRENT-OASIS 7 and PLATO. Prospective studies are required to determine whether individual PPIs are associated with adverse outcome and whether similar interactions occur with other thienopyridines (such as prasugrel).